GETTING FROM THE LAB TO IND

The IND (Investigational New Drug Application) seeks the FDA's authorization for the first administration of an experimental drug to humans. Because the IND must outline the initial thinking about the compound's entire clinical development, this first formal communication with the FDA (a.k.a. the agency) is of crucial importance.

COMPONENTS OF THE IND

The FDA web site offers extensive information on the form and content of an IND, as well as other pertinent documents. See http://www.fda.gov/cder/regulatory/applications/ for a general overview and helpful links.

The major components of the IND are as follows:

  • The Introductory statement and general investigational plan is a 2-3 page overview of the compound and a summary of its intended development. The emphasis is on describing the general design and goals of the first proposed human study.
  • The investigator's brochure is a stand-alone document of about 50 -- 100 pages which provides a comprehensive review of the compound. The brochure is written for clinical investigators who will perform the human studies involving the compound as well as their IRBs (institutional review boards), who must approve each study. The FDA has endorsed the ICH (International Conference on Harmonization) guidelines for the format and content of an investigators' brochure. These guidelines may be found within the following document: http://www.fda.gov/cder/guidance/959fnl.pdf.
  • The proposed initial protocol is the heart of the IND. When the FDA accepts an IND they are in effect giving permission to begin this first human (Phase I) study. The protocol does not have to be as detailed as for Phase II or III studies; the FDA is interested in an outline that includes key elements such as the number and type of subjects to be enrolled and the dosing schedule. Greater detail is reserved for safetyrelated sections, e.g. how adverse events will be monitored, the sorts of toxicity that are expected, and the stopping and dose-adjustment rules.
  • The chemistry, manufacturing, and control (CMC) information section details the synthetic steps involved in manufacturing the compound and describes the analytical techniques that will be used to identify it as well as potential impurities. A distinction is made between active pharmaceutical ingredient (formally called drug substance) and drug product; the manufacture of each must be described separately. The active pharmaceutical ingredient (API) refers to the chemical compound; drug product is the actual formulation (e.g. intravenous solution, capsule, oral suspension) that will be administered in the Phase I study. The focus of the CMC section is to convince the agency that both API and drug product are adequately characterized as to strength, purity, and stability to justify administration to humans.
  • The pharmacology and toxicology information section summarizes the animal data concerning the pharmacologic actions of the drug, as well as its safety. It is composed of two major sub-sections:
    • Pharmacology and drug distribution, a 5-6 page summary of 1) the drug's pharmacologic effects and mechanism of action and 2) the absorption, distribution, metabolism, and excretion (ADME) of the drug in one or more animal species.
    • Toxicology integrated summary, is a fairly hefty section, usually 10 -- 15 pages long, plus supplementary tables and figures. There are no precise requirements for toxicology studies, not even for the animal species to be tested. The sponsor is expected to make and justify such decisions based on the nature of the compound, its proposed human use, its probable toxicities, and the design of the Phase I study that will be supported. The goal is to present a package that will convince the agency that the drug is likely to be safe in the population and for the indication in which it will be tested.

ASSEMBLING THE IND

Once the decision has been made to file an IND, a major milestone in the life of a company, any delays can seem intolerable. It is important to plan how the required information will be generated so that the document can be assembled as efficiently as possible.

The investigator's brochure (IB) cannot be completed until all the other components of the IND are available, as it includes summaries of pharmacology, chemistry, manufacturing and toxicology. Usually the pharmacology and chemistry portions of the IB can be written up relatively early since the relevant work is generally complete before the decision is made to file the IND. To speed up IB production the other sections of the IB may be written, at least in outline form, before the final data are available. Toxicology testing is often the rate-limiting step in IND filing. Not only must the animal studies be planned and completed, but subsequently the histology must be evaluated, plasma drug levels assayed, and preliminary data tables and reports complied.

A company filing its first IND must usually contract out much of the work. This typically includes (1) manufacturing the drug substance and product, (2) developing the analytical techniques for assaying the compound, metabolites and contaminants, (3) performing and analyzing the toxicology studies, and (4) designing the initial human protocol and 5) often, even writing and assembling the IND itself. There is no shortage of contract research organizations (CRO) available to help. The challenge is finding the right one. Apart from the basic issues of cost and relevant expertise, there must be a good fit in terms of style.

One approach is to work with a large CRO that will take charge of the entire process, including managing any necessary sub-contracting. Indeed, some promise a turnkey operation---just hand over your compound and they will do everything up to and including actually filing the IND. The other approach is to select more specialized, usually smaller CROs with expertise in a relatively limited area such as regulatory filings, toxicology, manufacturing, or designing and carrying out Phase I studies in a specific therapeutic area (e.g. oncology). When taking this second route, it is necessary to actively manage and coordinate the work of multiple contractors. For example, the company must be sure that drug product and the appropriate analytical techniques are available in time to allow the toxicokinetic component of toxicology studies to proceed without delay. Coordination can be handled either in-house or by a consultant familiar with all aspects of the IND process.

THE IMPORTANCE OF EXPERT REGULATORY PLANNING AND ADVICE

No matter which method the company takes - using one major CRO, multiple smaller ones, or a hybrid of the two approaches - the key to a successful IND filing is the advice of an individual or group with extensive regulatory experience. Ideally they would have previously dealt with the Division of the FDA that will process the IND and supervise the subsequent New Drug Application (NDA). Each Division (e.g. Cardio-Renal, Oncology, Pulmonary) has its own style of interacting with the sponsoring company and its own interpretation of the regulations; having an advocate who has a personal relationship with the relevant FDA Division members is invaluable in enhancing the chances of a successful IND submission. For example, the IND toxicology requirements of each Division can vary considerably; a knowledgeable consultant can suggest a package that the Division is likely to accept that may be less extensive than the regulations appear to require.

A company should request a pre-IND meeting with the agency to discuss key components of the proposed application, particularly the Phase I study and subsequent development plans. Having an experienced individual to represent the company's interests at such a meeting is invaluable. He or she can help secure the FDA's agreement on specific IND contents, negotiate agreements on what data might be deferred until after the IND is submitted, and 'read' the agency's attitude on specific issues that arise.